The present invention relates to 2-deoxy derivatives of N-acetylneuraminic acid and to methods of their preparation.
Sialic acids, nonulosaminic acids, are a family of amino sugars that are derivatives of N-acetylneuraminic acid (Neu5Ac). Sialic acids are widely distributed through the animal kingdom and play many important roles in molecular recognition. Schauer, R. Adv. Carbohydr. Chem. Biochem. 40 (1982) 131. Schauser, R., "Sialic Acids," Springer-Verlag: Wein and New York, 1982. Howe, C., Lee, L. T. Adv. Virus Res. 17 (1982) 1. Also, certain types of cancer cells have been shown to contain higher levels of sialic acids than the corresponding normal cells. Van Boeckel, C. A. A. Recl. Trav. Chim. Pays-Bas 105 (1986) 35. Yogees Waren, G., Salk, P. C. Science (Washington, D.C.) 212 (1981) 1514.
Neu5Ac derivatives are useful as glycosyl donors for the enzymatic syntheses of oligosaccharides present in glycoproteins and glycolipids via CMP-Neu5Ac. David, S., Auge, C. Pure Appl. Chem. 59 (1987) 1501. Higa, H. H., Paulson, J. C. J. Biol. Chem. 260 (1985) 8838. Conradt, H. S., Buensch, A., Brossmer, R. FEBS Lett. 170 (1984) 295. Neu5Ac derivatives also are useful as enzyme inhibitors. Thiem, J., Treder, W. Angew. Chem., Int. Ed. Engl. 25 (1986) 1096. Sabesan, S., Paulsen, J. C. J. Am. Chem. Soc. 108 (1986) 2068. For example, 2-deoxy-Neu5Ac may be an inhibitor of CMP-Neu5Ac synthetase, a key enzyme in the biosynthesis of glyconjugates.
Neu5Ac and derivatives currently are prepared from natural sources. Schauer, R. Adv. Carbohydr. Chem. Biochem. 40 (1982) 131. Schauer, R. "Sialic Acids," Springer-Verlag: Wien and New York, 1982. Enzymatic aldol condensations provide an efficient alternative for asymmetric C--C coupling, which is one of the most interesting and challenging problems in synthetic organic chemistry. Whitesides, G. M., Wong, C. H. Angew. Chem. Int. Ed. Engl. 24 (1985) 617. Wong, C. H. in "Enzymes as Catalysts in Organic Synthesis," Schneider, M. P., Ed.; Reidel; Dordrecht, Holland, 1986; pp 199-216. Bednarski, M. D., Crans, D. C., Discosimo, R., Simon, E. S., Stein, P. D., Whitesides, G. M. Tetrahedron Lett., in press. Effenberger, F., Straub, A. Tetrahedron Lett. 28 (1987) 1641. Durrwachter, J. R., Druekhammer, D. G., Nozaki, K., Sweers, H. M., Wong, C. H. J. Am. Chem. Soc. 108 (1986) 7812. Masamune, S., Choy, W., Peterson, J. S., Sita, L. R. Angew. Chem., Int. Ed. Engl. 24 (1985) 1. Evans, D. A. Aldrichimica Acta 15 (1982) 23. Evans, D. A., Nelsh, J. V., Tabar, T. R. Top. Sterochem. 13 (1982) 1 . Most of the current methods used in the aldol reaction, however, depend upon the formation of metal-enolate complexes, which are unstable in aqueous media.
Although several chemical methods are available for synthesis of Neu5Ac and derivatives, many of the methods are expensive and may require complex protection and deprotection methods. Julina, R., Muller, I., Vasella, A., Wyler, R. Carbohydr. Res. 164 (1987) 415. Danishefsky, S. J., DeNinno, M. P. J. Org. Chem. 51 (1986) 2615. Conforth, J. W., Firth, M. G., Cottscalk, A. Biochem. J. 68 (1958) 57.